Substituted phenyl piperidines

ABSTRACT

Compounds of the formula ##STR1## wherein n is 1 or 2, Y is OH, R 1  COO--, R 2  R 3  NCOO-- or R 4  O whereby R 1  is an alkyl group, or a possibly substituted phenyl group, R 2  is an alkyl, phenethyl, benzyl or phenyl group, R 3  is H or an alkyl group and R 4  is an allyl or benzyl group, and R is an alkyl, hydroxyalkyl, dimethylaminoalkyl or methylthioalkyl group or alkenyl group, processes for their preparation and pharmaceutical preparations and methods of treatment employing such compounds. The compounds are useful for therapeutic purposes, especially for treatment of disorders in the central nervous system.

DESCRIPTION

1. Technical field

The present invention is related to new substitutedphenyl-azacycloalkanes, to processes for preparing such compounds aswell as to pharmaceutical preparations thereof and methods of treatmentemploying such compounds.

An object of the invention is to provide compounds for therapeutic use,especially having a therapeutic activity in the central nervous system.

2. Background Art

In Chemical Abstracts 69: 86776s (citing Julia, M. et al., Bull. Soc.Chim. Fr. 1968, (3), 1000-7) compounds under the general formula##STR2## are described. Among the compounds mentioned are compoundswherein R^(I) represents m--OCH₃ and R^(II) represents H, CH₃, C₂ H₅,CH₂ C₆ H₅, CH₂ CH₂ C₆ H₅ or CH₂ CH₂ C₆ H₄ NO₂ (p) and wherein R^(I)represents m--OH and R^(II) represents CH₂ CH₂ C₆ H₅ or CH₂ CH₂ C₆ H₄NO₂ (p). Said compounds were prepared for investigation ofpharmacological properties.

Swiss Pat. No. 526,536 describes compounds under the formula ##STR3##wherein R^(I) represents H or OH and R^(II) represents H. The compoundsare claimed to have useful pharmacological properties especially asbroncholytic agents.

DE Offenlegungsschrift No. 2 621 536 describes compounds of the formula##STR4## wherein X^(I) is hydrogen or an acyl group and R^(I) is analkyl, alkenyl or phenylalkyl group. The compounds are claimed to havedopaminergic properties.

DISCLOSURE OF INVENTION

According to the present invention it has been found that novelcompounds of the formula ##STR5## wherein n is 1 or 2, Y is OH, R¹ COO,R² R³ NCOO-- or R⁴ O whereby R¹ is an alkyl group having 1-5 carbonatoms or a possibly substituted phenyl group, R² is an alkyl grouphaving 1-5 carbon atoms, a phenethyl, benzyl or phenyl group, R³ is H oran alkyl group having 1-5 carbon atoms, and R⁴ is an allyl or benzylgroup, and R is an alkyl group having 1-5 carbon atoms, a hydroxyalkyl,dimethylaminoalkyl or methylthioalkyl group having 2-6 carbon atoms inthe alkyl part and having the heteroatom bound in a position other thanthe 1 position, an alkenyl group having 3-5 carbon atoms other than a1-alkenyl group, as bases and pharmaceutically acceptable acid additionsalts thereof, are potent neuropharmacological agents. Thus saidcompounds are active as presynaptic dopamine receptor agonists whenadministered to animals including man. The compounds are thus useful fortreatment of disorders in the central nervous system, especiallypsychotic disorders in man. Further, among the compounds of theinvention are compoounds having a positiv inotropic cardiac effect,substantially lacking chronotropic effect. Such compounds are useful fortreatment of cardiac insufficiency.

An alkyl group may be a straight alkyl group or a branched alkyl grouphaving at least 3 carbon atoms.

A possibly substituted phenyl group R¹ may be a phenyl,2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or4-alkanoyloxyphenyl group with the formula ##STR6## wherein R⁵ is analkyl group having 1-6 carbon atoms.

Symbols for numbers, atoms or groups referred to below have the broadestmeaning previously assigned unless specified otherwise.

Both organic and inorganic acids can be employed to form non-toxicpharmaceutically acceptable acid addition salts of the compounds of thisinvention. Illustrative acids are sulfuric, nitric, phosphoric,hydrochloric, citric, acetic, lactic, tartaric, pamoic,ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric,maleic and benzoic acid. These salts are readily prepared by methodsknown in the art.

In a restricted embodiment the invention is related to compounds of theformula I above wherein n is 1 or 2, Y is OH, R¹ COO-- or R² R³ NCOO--,whereby R¹ is an alkyl group having 1-5 carbon atoms, or a phenyl group,and R² is an alkyl group having 1-5 carbon atoms, a phenethyl, benzyl orphenyl group, and R³ is H or an alkyl group having 1-5 carbon atoms, andR is an alkyl group having 1-5 carbon atoms, a hydroxyalkyl group having2-6 carbon atoms in the alkyl part other than a 1-hydroxyalkyl group, analkenyl group having 3-5 carbon atoms other than a 1-alkenyl group.

According to a preferred embodiment the invention is related tocompounds of the formula I wherein n is 2 and Y and R are as specifiedabove.

Preferred compounds are those wherein Y is OH or R¹ COO or R⁴ O. Furtherpreferred are compounds wherein R is an alkyl group having 3-5 carbonatoms.

The compounds of the invention contain an asymmetric carbon atom in theheterocyclic ring moiety. The therapeutic properties of the compoundsmay to a greater or lesser degree be ascribed to either or both of thetwo enantiomers occurring. Thus the pure enantiomers as well as mixturesthereof are within the scope of the invention.

The invention takes into consideration that compounds which structurallydeviates from the formula I, after administration to a living organismmay be transformed to a compound of the formula I and in this structuralform exert their effects. This consideration is a further aspect of theinvention. Likewise, certain compounds of formula I may be metabolizedinto other compounds of formula I before exerting their effect.Compounds of the invention wherein Y is R¹ COO, R² R³ NCOO or R⁴ O arethus believed to exert their main activity after metabolism to compoundswherein Y is OH.

METHODS OF PREPARATION

The compounds of the invention may be obtained by one of the followingmethods constituting a further aspect of the invention.

(a) An ether or ester of the formula ##STR7## wherein R^(a) represents ahydrocarbon or acyl residue, preferably an alkyl group having 1-5 carbonatoms, or an alkyl-carbonyl group having 2-6 carbon atoms, and n and Rare as defined above, may be cleaved to form a compound of formula Iwherein Y is a hydroxy group.

When R^(a) is a hydrocarbon residue the cleavage may be carried out bytreating the compound of formula II with an acidic nucleophilic reagentsuch as aqueous HBr, or HI,HBr/CH₃ COOH, BBr₃, AlCl₃, pyridine-HCl or(CH₃)₃ SiI, or with a basic nucleophilic reagent such as CH₃ C₆ H₄--S.sup.⊖ or C₂ H₅ --S.sup.⊖.

When R^(a) is an acyl residue the cleavage may be carried out byhydrolysis in an aqueous acid or base or by reduction, preferably byLiAlH₄.

(b) In a compound of the formula ##STR8## wherein Z represents SO₃ H, Clor NH₂, a hydroxy group may be substituted for the group Z to theformation of a compound of formula I wherein Y represents a hydroxygroup. When Z is SO₃ H or Cl said reaction may be carried out bytreatment with a strong alkali under heating, suitably with an alkalimelt such as KOH when Z is SO₃ H, and with a strong aqueous alkali suchas NaOH or KOH when Z is Cl. When Z is NH₂ the reaction may be carriedout by treatment with aqueous nitrous acid to the formation of anintermediate diazonium compound which is then subjected to hydrolysis inwater.

(c) A compound of formula I ##STR9## wherein Y is OH and R is other thanhydroxyalkyl may be converted into a compound of the same formulawherein Y is R¹ COO, R² R³ NCOO or R⁴ O by treating the firstmentionedcompound with an appropriate carboxylic acid halide R¹ COX or anhydride(R¹ CO)₂ O or with an appropriate carbamoyl halide R² R³ NCOX orisocyanate R² NCO in the presence of a base such as triethylamine orpyridine or an acid such as H₂ SO₄ or CF₃ COOH or with an appropriateallyl or benzyl halide R⁴ X in the presence of a base such astriethylamine, pyridine or potassium t-butoxide. X represents a halogen,preferably Cl or Br.

Alternatively, when conversion of Y=OH into R¹ COO is intended and R¹ is##STR10## a compound of formula I wherein Y is OH may first be convertedto a compound of formula I wherein Y is ##STR11## which is then treatedwith an appropriate carboxylic acid halide R⁵ COX or anhydride (R⁵ CO)₂O in the presence of a base or an acid.

(d) A compound of the formula ##STR12## may be converted into a compoundof formula I by alkylation of the nitrogen atom with an appropriatealkylating agent. Thus, the starting compound may be treated with analkyl, hydroxyalkyl, dimethylaminoalkyl, methylthioalkyl, alkenyl orbenzyl halide or tosylate RX¹, wherein X¹ represents Cl, Br, I or##STR13## in an organic solvent such as acetonitrile or acetone and inthe presence of a base such as K₂ CO₃ or NaOH, or the starting compoundmay be treated with a carboxylic acid NaBH₄ complex R^(b) COOH--NaBH₄,wherein R^(b) is defined by the relation R^(b) --CH₂ -equals R. To theformation of a compound of formula I wherein R is CH₃, which is notobtainable by the last-mentioned reaction, the alkylation reaction maybe carried out by treatment with a formaldehyde --Na(CN)BH₃ mixture. Tothe formation of a compound of formula I wherein R is hydroxyalkyl,dimethylaminoalkyl or methylthioalkyl the synthesis may also be carriedout by alkylation with an appropriate dihaloalkane giving amonohaloalkyl derivative of I followed by acid or alkaline hydrolysisand reaction with dimethylamine or CH₃ S.sup.⊖. Especially, to theformation of a compound of formula I wherein R is 2-hydroxyalkyl, thealkylation may also be carried out by reaction with a 1,2-epoxyalkane.

(e) An amide- or imide-containing compound of the formula ##STR14##wherein M¹ and M² are the same or different and each represents --CH₂ --or >C═O, and M³ is ##STR15## when M¹ and M² are both --CH₂ --, and inother cases M³ is R. R^(c) is H, an alkyl or alkoxyl group containing1-4 carbon atoms, a hydroxyalkyl, dimethylaminoalkyl or methylthioalkylgroup containing 1-5 carbon atoms, or an alkenyl group containing 2-4carbon atoms, and R^(d) is H, R¹ CO, allyl or benzyl may be convertedinto a compound of the formula I wherein Y is a hydroxy, allyl or benzylgroup by reduction of the amide or imide function, and the esterfunction R¹ COO if present. Thus the compound of formula IV may betreated with a reducing agent, preferably a hydride reducing agent suchas LiAlH₄ or BH₃ in an etheral solvent or a metal reducing agent such asNa in an alcoholic solvent such as n-butanol.

(f) A compound of the formula ##STR16## wherein R^(e) is H or benzyl andwherein R is an alkyl or hydroxyalkyl, dimethylaminoalkyl ormethylthioalkyl group as further defined above, may be converted eitherby direct reduction or by first elimination of the tertiary alcohol toan intermediary 1-cycloalkenyl compound and then reduction into acompound of formula I wherein Y is OH and R is as just defined. Thereduction may preferably be carried out by catalytic hydrogenation witha catalyst such as Pd or PtO₂, and the elimination reaction by heatingin the presence of an acid.

(h) A compound of the formula ##STR17## wherein Y¹ is benzyloxy or Y,wherein Y is as originally defined, however, other than O-allyl, and Ris an alkyl group containing 1-5 carbon atoms or a hydroxyalkyl,dimethylaminoalkyl or methylthioalkyl group containing 2-6 carbon atomsand having the heteroatom bound in a position other than the 1-position,may be converted by reduction into the corresponding compound of formulaI wherein n is 2. When Y¹ is benzyloxy a compound of formula I wherein Yis OH is obtained. The reduction may preferably be carried out bycatalytic hydrogenation using a catalyst such as PtO₂, or by reductionwith NaHB₄ followed by catalytic hydrogenation.

(i) A compound according to the formula ##STR18## wherein one of thegroup Z¹ and Z² is a leaving group, X and the other is NHR, or Z¹ and Z²are both leaving groups X, and X is a leaving group such as Cl, Br, I or--OSO₂ C₆ H₄ CH₃, may be converted to a compound of formula I wherein Yis OH by treating the compound of formula VIII, or when one of Z¹ and Z²is NHR an acid addition salt thereof, with a base such as (C₂ H₅)₃ N orK₂ CO₃, whereby the compound of formula VIII is treated together with anequivalent amount of an amine R--NH₂ or an acid addition salt thereofwhen Z¹ and Z² are both X. The conversion is carried out in a solventsuch as tetrahydrofuran, dioxan or acetonitrile, if necessary withsimultaneous or subsequent heating of the mixture.

Free bases formed may subsequently be converted into their acid additionsalts, and acid addition salts formed may subsequently be converted intothe corresponding bases or other acid addition salts.

PREPARATION OF STARTING MATERIALS

Starting materials for the methods of preparation described above may beobtained by several methods known in the art or described below.

The starting material for method (a) according to formula II above maybe prepared by one of the following methods: ##STR19##

A compound of formula IX, wherein R^(a) is an alkyl group having 1-5carbon atoms, is reduced e.g. with LiAlH₄. In the compound X formed, agroup R may then be introduced in analogy with the procedure of method(d) above or by modification of the first step in analogy with method(e) above. ##STR20##

In a compound of formula XI, obtainable by method (E2) below, themethoxy group is split off with HBr, whereupon a protective group R^(a)being an alkyl group having 1-5 carbon atoms or an acyl group having 2-6carbon atoms, is substituted in the hydroxy group by reaction with ahalide R^(a) X in the presence of a base. The compound thus formed isthen hydrogenated to the formation of a compound of formula II wherein nis 2 and R^(a) is as just defined with previous (method H) or subsequent(method A1) introduction of a group R.

The starting material for method (b) may be prepared by one of thefollowing methods ##STR21##

In a compound of formula XIII a group R may be introduced as previouslydescribed whereupon the compound is treated with Cl₂ or H₂ SO₄ to theformation of an isomeric mixture XIV, from which the compound IIIwherein Z is Cl or SO₃ H is obtained by chromato-graphic separation.##STR22##

The compound of formula XV is hydrogenated under acidic conditions inthe presence of PtO₂ to give a phenylpiperidine which is N-acylated withan appropriate carboxylic acid chloride R^(f) COCl wherein R^(f) is analkyl group having 1-4 carbon atoms or an ethoxy group, in the presenceof a base such as triethylamine, giving an amide, which is subjected tomild acid or basic hydrolysis of the ester function giving a compoundXVI. Said compound XVI is treated with ClCOOC₂ H₅ and triethylamine andthen with sodium azide giving a carboxylic acid azide which on heatinggives the isocyanate XVII. The isocyanate is treated with an excess ofboiling benzyl alcohol giving a carbamate which is then hydrogenated inthe presence of Pd/C to give a compound XVIII. A compound of formula IIIwherein Z is NH₂ and n is 2 is then formed by subjecting the amide groupof compound XVIII to splitting with an aqueous acid or base when anN-unsubstituted compound is desired, to reduction with e.g. LiAlH₄ whenR=an alkyl group having 2-5 carbon atoms is desired. When R=CH₃ isdesired a compound XVIII wherein R^(f) is an ethoxy group may be treatedwith LiAlH₄.

The starting materials for method (e) may be prepared by one of thefollowing methods ##STR23##

A compound of formula XIX may be formed by N-acylation of acorresponding compound of formula X, preparable according to A1 above,with an acid chloride R^(c) COCl in the presence of a base. The etherfunction of compound XIX is then cleaved with BBr₃ to the formation of acompound of formula IV wherein M¹ and M² are both --CH₂ -- and R^(d) isH. If desired the hydroxy group may then be acylated with an acylchloride to form a compound of formula IV wherein R^(d) is R¹ CO, oralkylated with an allyl or benzyl halide to form a compound of formulaIV wherein R^(d) is allyl or benzyl. ##STR24##

A compound of formula XX wherein R^(a) is alkyl having 1-5 carbon atomsis reacted with I(CH₂)_(n) COOC₂ H₅, or alternatively when n=2 isdesired with CH₂ =CH--COOC₂ H₅, in the presence of a base to theformation of a compound of formula XXI. When n=1 is desired compound XXImay be prepared by the following route. ##STR25##

The compound obtained by reaction of the alkoxy-benzaldehyde withdiethylmalonate is reacted with KCN in ethanol to the formation of acompound XXI wherein n is 1.

The compound XXI obtained by one of said routes is then converted into acompound of formula IV along the following route. ##STR26##

Compound XXI is treated with hydrogen in the presence of a catalyst suchas Raney nickel to the obtention of compound XI, in which a substituentis introduced at the nitrogen atom, if required in the end compound, bymeans of a halide RX. The ether function is then cleaved with BBr₃giving a compound IV wherein R^(d) is H and M¹ is --CH₂ -- and M²is >C=O and, if required in compound IV, the hydroxy group is acylatedwith an acyl chloride R¹ COCl in the presence of a base, or alkylatedwith an allyl or benzyl halide to form a compound of formula IV whereinR^(d) is allyl or benzyl. ##STR27##

A compound of formula XXIV is reacted with I(CH₂)_(n) CN, oralternatively when n=2 is desired with CH₂ =CH--CN, in the presence of abase, to the formation of a compound XXV. The subsequent route forpreparation of the compound IV wherein M¹ is >C=O and M² is --CH₂ -- iscompletely analogous to the route XXI to IV described above. ##STR28##

A compound of formula IV wherein M¹ is >C=O, M² is --CH₂ --, M³ is R,R^(d) is H and n is 1 or 2 may be prepared by oxidation of a compound offormula VI above e.g. with Br₂. ##STR29##

A compound of formula XXI is heated with an aqueous acid to theformation of a dicarboxylic acid XXVI, which is then reacted with aceticacid anhydride. Heating of the resulting cyclic anhydride with an amineR--NH₂ yields an imide XXVII, in which the ether function is cleavedwith BBr₃ giving a compound IV wherein R^(d) is H and M¹ and M² areboth >C=O, and, if required, the hydroxy group is acylated to theformation of compound IV, wherein R^(d) is R¹ CO, or alkylated with anallyl or benzyl halide to form a compound of formula IV wherein R^(d) isallyl or benzyl.

The starting material for method (f) may be prepared by the followingmethod. ##STR30##

A Grignard reaction with compounds XXVIII and XXIX produces compound V.The compound XXIX may be prepared by reacting a compound of the formula##STR31## with an alkyl bromide RBr in the presence of a base such as K₂CO₃ when an alkyl group R is required.

Starting material for method (h) may be prepared by the followingmethod. ##STR32##

When a group Y¹ other than hydroxy is required, such a group isintroduced by reaction of a compound XII with an appropriate acyl,carbamoyl, benzyl or allyl chloride in the presence of a base. Thepyridyl nitrogen is then reacted with a hydrogen halide or alkyl halideRX¹ (X¹ =Br or I) to the formation of an ion VII.

Starting materials for method (i) may be prepared by one of thefollowing methods. ##STR33##

A compound of formula XXI, obtainable according to method E2), isreduced with LiAlH₄ to the formation of compound XXX, which isN-substituted with a halide RX¹, wherein X¹ is a halogen, in thepresence of a base. In the compound obtained the ether function iscleaved with aqueous HBr to the formation of a compound XXXI. A leavinggroup X is then introduced to the formation of compound VIII, wherein Z¹is NHR and Z² is X, by reaction with thionyl chloride, whereby X=Cl isobtained, or with an acid HX. ##STR34##

A compound of formula XXV, obtainable according to method (E3), isconverted into a compound of formula VIII, wherein Z¹ is X and Z² isNHR, in a manner analogous to the conversion XXI to VIII under (I1)above. ##STR35##

A compound of formula XXVI, obtainable according to method (E4), isreduced with LiAlH₄. In the resulting compound the ether function iscleaved with aqueous HBr to the formation of a compound of formulaXXXII. In compound XXXII two leaving groups X are introduced to theformation of a compound VIII, wherein Z¹ and Z² are each X, by reactionwith thionyl chloride, whereby X=Cl is obtained, or with an acid HX.

Intermediates

Some of the intermediates or starting materials mentioned above and thepreparation thereof are known. However, certain intermediates orstarting materials are novel and constitute a further aspect of theinvention. Thus in one aspect the invention is related to novelcompounds of the formula ##STR36## wherein Z³ is R or R⁶ CO wherein R⁶is an alkyl or alkoxy group containing 1-4 carbon atoms or an alkenylgroup with 2-4 carbon atoms, R⁷ is an alkyl group with 1-5 carbon atomsan allyl or benzyl group and n is 1 or 2 provided that Z³ is other thanmethyl and ethyl when n is 2 and R⁷ is CH₃, as well as to acid additionsalts (where possible) of said compounds, and to the methods forpreparing said compounds or salts.

PHARMACEUTICAL PREPARATIONS

Pharmaceutical preparations of the compounds of the invention constitutea further aspect of the invention.

In clinical practice the compounds of the present invention willnormally be administered orally, rectally, or by injection, in the formof pharmaceutical preparations comprising the active ingredient eitheras a free base or as a pharmaceutically acceptable non-toxic, acidaddition salt, e.g. the hydrochloride, lactate, acetate, sulfamate, andthe like, in association with a pharmaceutically acceptable carrier.

Accordingly, terms relating to the novel compounds of this invention,whether generically or specifically, are intended to include both thefree amine base and the acid addition salts of the free base, unless thecontext in which such terms are used, e.g. in the specific examples,would be inconsistent with the broad concept. The carrier may be asolid, semisolid or liquid diluent or capsule. These pharmaceuticalpreparations constitute a further aspect of this invention. Usually theactive substance will constitute between 0.1 and 99% by weight of thepreparation, more specifically between 0.5 and 20% by weight forpreparation intended for injection and between 0.2 and 50% by weight forpreparations suitable for oral administration.

Pharmaceutical preparations containing a compound of the invention in asolid form of dosage units for oral application may preferably containbetween 2 and 50% by weight of the active substance, in suchpreparations the selected compound may be mixed with a solid fine graincarrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such aspotato starch, corn starch or amylopectin, cellulose derivatives, orgelatin and a lubricant such as magnesium stearate, calcium stearate,polyethylene glycol waxes, and the like, and then compressed to formtablets. If coated tablets are required, the cores, prepared asdescribed above, may be coated with a concentrated sugar solution whichmay contain, e.g. gum arabic, gelatin, talcum, titanium dioxide, and thelike. Alternatively the tablet can be coated with a lacquer dissolved ina readily volatile organic solvent or mixture of organic solvents.Dyestuffs may be added to these coatings in order to readily distinguishbetween tablets containing different active substances or differentamounts of the active compound.

For the preparation of soft gelatin capsules (pearl-shaped closedcapsules) consisting of gelatin and, for example, glycerol, or similarclosed capsules, the active substance may be admixed with a vegetableoil. Hard gelatin capsules may contain granulates of the activesubstance in combination with solid, fine grain carriers such aslactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch,corn starch or amylopectin), cellulose derivatives or gelatin.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing from about 0.2% to about20% by weight of the active substance herein described, the balancebeing sugar and a mixture of ethanol, water, glycerol andpropyleneglycol. Optionally such liquid preparations may containcolouring agents, flavouring agents, saccharine andcarboxymethylcellulose as a thickening agent.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance preferably in a concentration of from about 0.5% toabout 10% by weight. These solutions may also contain stabilizing agentsand/or buffering agents and may conveniently be provided in variousdosage unit ampoules.

In therapeutical treatment the suitable daily doses of the compounds ofthe invention are 200-10000 mg for oral application, preferentially1000-6000 mg, and 1-1000 mg for parenteral application, preferentially50-500 mg.

WORKING EXAMPLES

The following examples will further illustrate the invention.

PREPARATION OF INTERMEDIATES Example I1.N-Butyl-3-(3-methoxyphenyl)piperidine hydrochloride (Method A1 and e)

Butyryl chloride (2.0 g, 0.019 mol) in dry toluene (5 ml) was slowlyadded to a solution of 3-methoxyphenylpiperidine (2.45 g, 0.013 mol) andtriethylamine (1.92 g, 0.013 mol) in dry toluene at 5°. The mixture wasstirred at room temperature for 30 min., whereupon the triethylammoniumchloride formed was filtered off and the solvent evaporated. The crudeN-butyryl-3-(3-methoxyphenyl)piperidine (2.82 g) dissolved in drytetrahydrofuran (30 ml) was added to a suspension of LiAlH₄ (2.0 g) indry tetrahydrofuran (30 ml) under nitrogen. After reflux for 3 h in themixture was hydrolysed, the precipitate filtered off and the solventevaporated. The residue dissolved in light petroleum was passed throughan alumina column. (Alternatively the residue could be distilled invacuo). The product was precipitated as the hydrochloride andrecrystallized from ethanol/ether yielding the pure product (3.6 g, 88%)mp 130°-1° C.

EXAMPLE I2. N-Propyl-3-(3-methoxyphenyl)pyrrolidine (Method A1 and e)

3-(3-Methoxyphenyl)pyrrolidine (8.86 g, 0.050 mol) and triethylamine(5.57 g, 0.055 mol) was dissolved in 500 ml of dry ether. The solutionwas cooled to 0° C. and propionyl chloride (5.09 g, 0.055 mol) was addeddropwise with stirring. The reaction mixture was then allowed to acquireambient temperature, whereafter it was refluxed for 30 minutes.Triethylamine hydrochloride was filtered off, and the filtrate wasevaporated leaving 11.7 g (100%) of crudeN-propionyl-3-(3-methoxyphenyl)pyrrolidone, which was used in the nextreaction step without further purification. The crude amide (11.7 g,0.050 mol) was reduced with LiAlH₄ (2.85 g, 0.075 mol) in refluxingether (200 ml) for 24 hours. Work-up of the reaction mixture afforded 10g of product, which upon distillation in vacuo yielded 9.1 g ((83%) ofN-propyl-3-(3-methoxyphenyl)-pyrrolidone b.p. 85°-86° C./0.1 mm Hg. MS:m/e 219 (M⁺, 12%) 190 (M--C₂ H₅, 100%).

EXAMPLE I3. N-Pentyl-3-(3-methoxyphenyl)piperidine (Method A1 and d)

To a solution of 3-(3-methoxyphenyl)piperidine (3.92 g, 0.02 mol) in CH₃CN (100 ml), solid K₂ CO₃ (5 g) was added and then the mixture wasrefluxed. A solution of pentyliodide (4.5 g, 0.021 mol) in CH₃ CN (10ml) was added dropwise under 30 min. and then the mixture was refluxedfor an additional 30 min. The solid was filtered off from the cooledmixture, and the solvent evaporated giving an oil which waschromatographed on a silica gel column with methanol as eluant. Yield1.3 g (25%) of pure N-pentyl-3-(3-methoxyphenyl)piperidine (NMR) as anoil.

EXAMPLE I4. N-Propyl-3-(3-methoxyphenyl)piperidine hydrochloride (MethodA1 and d)

NaBH₄ (6.08 g, 0.16 mol) was added portionwise under stirring to asolution of propionic acid (38 g, 0.51 mol) in dry benzene (150 ml). Thetemperature was kept below 15° C. for 2 h and then3-(3-methoxyphenyl)-piperidine (6.1 g, 0.032 mol) dissolved in drybenzene (100 ml) was added and the mixture was refluxed for 3 h. Thereaction mixture was allowed to reach room temperature and was thenextracted with 2.5 M NaOH (200 ml). The aqueous phase was extracted withbenzene, all the benzene phases mixed, dried (Na₂ SO₄) and the solventevaporated giving an oily residue (6.6 g). The product was precipitatedas hydrochloride and recrystallized from methanol/isopropyl etheryielding the pure product (6.2 g, 72%). mp. 191° C.

EXAMPLE I6. N-Propyl-3-(3-methoxyphenyl)piperidine hydrobromide (MethodA2 and h)

3-(3-pyridinyl)methoxybenzene (3.0 g, 0.016 mol) and propyl bromide (2.0g) was dissolved in dry acetone (50 ml) and allowed to react at 110° C.in a high pressure steel vessel. After 20 h the reaction was interruptedand the solvent was evaporated. The residual quarternaryN-propyl-3-(3-methoxyphenyl)pyridinium bromide was hydrogenated (PtO₂)in methanol at r.t. and 760 mmHg. The H₂ -uptake ceased after 24 h. Thecatalyst was filtered off and the solvent evaporated. The hydrobromidewas recrystallized from ethanol/ether giving 2.63 g (70%) of the pureproduct, mp. 155°-156° C.

EXAMPLE I7. 3-(3-Pyridinyl)methoxybenzene (Method A2)

This substance was prepared by a dichlorobis-(triphenylphosphine)nickel(II) catalyzed reaction between 3-methoxyphenylmagnesium bromide (from50 g of 3-bromo-anisole and 5.9 g of Mg in THF) and 31.8 g of3-bromopyridine. Yield 23.1 g (62%), bp. 102°/0.15 mmHg, mp. (HCl)187.5°-9° C.

EXAMPLE I8. 3-(3-Methoxyphenyl)piperidine hydrochloride (Method A2 andh)

To a solution of 3-(3-pyridinyl)methoxybenzene (22.0 g, 0.099 mol) inmethanol (250 ml), PtO₂ (2 g) and conc. HCl (30 ml) were added and themixture was hydrogenated at 0.34 MPa in a Parr apparatus. After completehydrogenation, the catalyst was filtered off. Most of the solvent wasevaporated, the residue was made alkaline with 1 M NaOH and extractedwith ether. The ether-phase was dried (Na₂ SO₄) and the solventevaporated giving 18 g of the amine product. The hydrochloride was madeand then recrystallized from ethanol/ether yielding 20.9 g (93%), mp.137°-138.5° C.

EXAMPLE I9. N-n-Propyl-3-(3-aminophenyl)piperidine hydrochloride (MethodB2) 3-(3-Methylphenyl)-pyridine

3-(3-methylphenyl)-pyridine was prepared from 81.5 g (0.52 mol)3-bromopyridine and 120 g (0.70 mol) 3-bromotoluene as described for thepreparation of 3-(3-methoxyphenyl)-pyridine. (Example I7). B.p. 87°/0.05mmHg. Yield 61.7 g (69%).

METHYL-3-(3-pyridyl)-benzoate

A mixture of 3-(3-methylphenyl)-pyridine (30 g, 0.177 mol), potassiumpermanganate (67.5 g, 0.427 mol) and water (825 ml) was refluxed overnight with stirring. The hot mixture was filtered, acidified (conc. HCl)and evaporated in vacuo. After drying in the air the solid was dissolvedin HCl-saturated methanol (2500 ml), the resulting solution was refluxedfor 24 hours. The methanol was evaporated and the residue was madealkaline with saturated potassium carbonate solution. Extraction withether followed by drying (K₂ CO₃) and evaporation of the ether gave anoil which was distilled in vacuo. The fraction distilling from 90° C. to135° C. at 0.2 mm was then filtered through a SiO₂ -column with ether aseluant. Evaporation of the ether gave the pure product (21 g, 55%) as asolid.

The hydrochloride was prepared by dissolving the aminoester in etherfollowed by addition of HCl-saturated ether. The salt was recrystallizedfrom methanol/ether, mp. 208°-209° C.

3-(1-Propionylpiperidino-3-yl)-benzoic acid

A solution of the HCl-salt of methyl-3-(3-pyridyl)-benzoate (5.54 g,0.022 mol) in methanol was hydrogenated (atm. pressure) at r.t. usingPtO₂ as catalyst. After filtration and evaporation the residue waspartitioned between a saturated potassium-carbonate solution and ether.The ether layer was dried (K₂ CO₃), cooled and treated withtriethylamine (2.23 g, 0.022 mol) and propionylchloride (2.05 g, 0.033mol). Stirring at r.t. for one hour followed by filtration andevaporation gave an oil which was eluated twice through an Al₂ O₃-column with ether. Evaporation of the ether gave 4.8 g of puremethyl-3-(1-propionylpiperidin-3-yl)benzoate as an oil, which could notbe crystallized.

A mixture of methyl-3-(1-propionylpiperidin-3-yl)benzoate (4.8 g, 0.017mol), sodium hydroxide pellets (5 g), methanol (80 ml) and water (20 ml)was stirred until TLC indicated that no starting material remained (4hours). The methanol was evaporated and the alkaline water layer waswashed with ether, acidified with hydrochloric acid and extracted withchloroform. Evaporation gave the product (4.0 g, 69% yield frommethyl-3-(3-pyridyl)-benzoate) as an oil which crystallized afterseveral weeks on standing. (Mp. 125°-126° C.).

N-propyl-3-(3-Aminophenyl)-piperidine hydrochloride

To a cooled (-10° C.) solution of 3-(1-propionylpiperidin-3-yl)benzoicacid (9.75 g, 0.036 mol) and triethylamine (3.56 g, 0.033 mol) inacetone (115 ml) ethyl chloroformate (4.34 g, 0.040 mol), was slowlyadded. After stirring at -10° C. for one and a half hour, a solution ofsodium azide (3 g, 0.046 mol) in water (10 ml) was added dropwise, andthe mixture was stirred at -10° C. for one hour more. The reactionmixture was poured into icewater and extracted with toluene. The tolueneextract was dried (MgSO₄) and heated until a small sample run on IRindicated that the reaction (the convertion of the acyl azide to theisocyanate) was complete. Evaporation of the toluene gave the isocyanateas an oil.

The isocyanate was boiled with benzyl alcohol (20 ml) until the reactionwas complete (IR; 24 hours). Evaporation of unreacted benzylalcohol gavean oil (1.5 g) which was dissolved in methanol and hydrogenated at r.t.and atmospheric pressure with 10% Pd/C as catalyst. Filtration andevaporation gave an oil which was further reacted with LiAlH₄ (1.0 g,0.026 mol) in tetrahydrofuran. Refluxing for 3 h followed by hydrolysisof the reaction mixture, filtration and evaporation of the solvent gavethe crude N-n-propyl-3-(3-aminophenyl)piperidine which was converted toits dihydrochloride by dissolving the base in methanol and saturatingthe solution with HCl. Evaporation of the methanol gave the salt as anoil. Yield: 0.40 g (4%, calculated on3-(1-propionylpiperidin-3-yl)benzoic acid). A sample of the oil wasreconverted to the base and dissolved in CDCl₃ for NMR (see table).

Preparation of end compounds Example E1.N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (Method a)

N-Propyl-3-(3-methoxyphenyl)piperidine hydrochloride (7.0 g, 0.026 mol)was suspended in 48% HBr (200 ml). The mixture was refluxed undernitrogen for 3 h. The hydrobromic acid was evaporated and the residuewas recrystallized from ethanol/ether, yielding the pure product (6.7 g,86%) mp. 146°-7.5° C.

Example E2. N-pentyl-3-(3-hydroxyphenyl)piperidine hydrochloride (Methoda)

N-Pentyl-3-(3-methoxyphenyl)piperidine (1.3 g, 0.005 mol) in CH₂ Cl₂ (20ml) was cooled with dry ice and BBr₃ (1.6 g, 0.006 mol) was addeddropwise. The mixture was then held at -78° C. for 1 h and then allowedto reach r.t. over night. The solution was made alkaline with aqueousNa₂ CO₃, extracted with CH₂ Cl₂ and the organic phase dried with Na₂SO₄. Evaporation of the solvent afforded an oily residue which wastreated with HCl-saturated ethanol (5 ml). After evaporation of solvent,purification by extractions and recrystallization (ethanol/ether), thedesired product (0.40 g, 29%) was obtained, mp. 70°-80° C.

Example E3. N-n-Propyl-3-(3-acetoxyphenyl)piperidine hydrochloride(Method c)

N-n-propyl-3-(3-hydroxyphenyl)piperidine (0.8 g, 0.0037 mol) wasdissolved in acetic anhydrice (20 ml). Triethylamine (1 ml) was addedand the solution was refluxed for 1.5 h, ethanol (50 ml) was added andthe volatiles were evaporated giving a residual oil. The residue waspartitioned between ether and water. Separation of the two phases andevaporation of the ether gave an oily residue (700 mg). This wasdissolved in dry ether (100 ml) and HCl-saturated ether was added givingthe desired compound as a crystalline precipitate, which was filteredoff and recrystallized from methanol/isopropyl ether. Yield 0.60 g(55%), mp. 173°-175° C.

Example E4. N-n-Propyl-3-(3-benzoyloxyphenyl)piperidine hydrochloride(Method c)

N-n-Propyl-3-(3-hydroxyphenyl)piperidine (0.5 g, 0.0023 mol) wasdissolved in CH₂ Cl₂ (50 ml). Triethylamine (1 ml) and benzoyl chloride(0.5 ml, 0.004 mol) was added and the mixture was stirred at r.t. for 48h. The solvent was evaporated and the residue was partitioned betweenether and water. The ether phase was dried (Na₂ SO₄) and the solventevaporated giving an oily residue which was eluated through a shortsilica gel column with methanol as eluant. Evaporation of the solventgave an oily residue (300 mg). The oil was dissolved in ether andHCl-saturated ether was added. Filtration and drying gave the desiredcompound in a crystalline form. Yield 13%, mp. 170° C.

Example E5. 2-[3-(3-Hydroxyphenyl)-piperidino]ethanol hydrochloride(Method d)

Ethylenoxide (0.36 ml, 7.0 mmol) was added to a stirred solution of3-(3-hydroxyphenyl)piperidine (1.0 g, 5.6 mmol) in methanol (150 ml),maintaining the temperature at -30° C., whereafter the reaction mixturewas allowed to reach room temperature. (The reaction was followed byTLC). More ethylenoxide (0.5 ml, 9.8 mmol) was added in portions untilthe reaction was complete (two weeks). An excess of ethereal hydrogenchloride was added and the solvent was evaporated. The oily residue waspassed through a silica column with 10% methanol in chloroform. Afterevaporation the hydrochloride was recrystallized from ethanol/ether toyield 0.6 g (41%) of 2-[3-(3-hydroxyphenyl)-piperidino]ethanolhydrochloride, m.p. 116.5°-120° C.

Example E6. N-n-Propyl-3-(3-hydroxyphenyl)piperidine hydrochloride(Method b)

To a solution of N-n-Propyl-3-(3-aminophenyl)piperidine (0.74 g, 0.0034mol) in 6M H₂ SO₄ (2 ml) NaNO₂ (0.23 g, 0.0034 mol) dissolved in water(0.6 ml) was added dropwise at 5° C. and then the mixture was stirred at5° C. for 1 h. The resulting mixture was added dropwise to refluxing 10%H₂ SO₄ (3.5 ml) and the reflux was continued for 5 min. Cooling,alkalising (Na₂ CO₃), extraction with ether, drying and evaporation ofthe organic phase gave the desired product as a free base. Conversion tothe hydrochloride followed by recrystallization gave 0.22 g (25%) ofN-n-propyl-3-(3-hydroxyphenyl)piperidine hydrochloride, mp. 143.5°-146°C.

Example E7. N-n-Propyl-3-(3-allyloxyphenyl)piperidine hydrochloride(Method e)

A solution of N-n-propionyl-3-(3-allyloxyphenyl)piperidine (0.35 g,0.0013 mol) in dried ether (25 ml) was dropped to a suspension of LiAlH₄(0.35 g) in dried ether under nitrogen and stirring, and the mixture wasrefluxed for 30 min. H₂ O (0.35 ml), 15% NaOH (0.35 ml) and H₂ O (1 ml)were added and the precipitated crystals were filtered off and washedwith ether. The solution was dried with Na₂ SO₉. Evaporation to drynessgave an oily residue which was dissolved in ether. Addition ofHCl-saturated ether resulted in precipitation of white crystals. Thecrystals were centrifugated and treated with light petroleum,centrifugated and dried. Yield 0.185 g (49%).

Example E8. N-n-Propyl-3-(3-benzyloxyphenyl)piperidine hydrochloride(Method c)

A mixture of N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (1.0g, 0.0033 mol), potassium t-butoxide (1.0 g, 0.009 mol) andbenzylchloride (1.0 g, 0.009 mol) in t-butanol (25 ml) was refluxed for1 h. Water was added and the mixture extracted with ether. The organicphase was dried with Na₂ SO₄ and evaporated to dryness giving a paleyellow oily residue. The residue was chromatographed through a silicagel column with methanol as eluant. The pertinent fractions werecollected and evaporated to dryness. The oily residue was dissolved inether and HCl-saturated ether was added, giving white crystals.Evaporation and treatment of the residue with acetone gave 0.60 g (52%)of the desired product as white crystals, mp. 171° C.

Example E9. N-n-Propyl-3-[3-(phenylcarbamoyloxy)phenyl]piperidinehydrochloride (Method c)

A mixture of N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (0.76g, 0.0025 mol), phenylisocyanate (5.45 g, 0.046 mol), triethylamine (0.5g, 0.049 mol) and methylene chloride (2 ml) was stirred at r.t. for 18h. The mixture was partitioned between water and ether. The ether phasewas dried and evaporated giving a partly crystalline residue. Theresidue was dissolved in methanol and chromatographed on a silica gelcolumn (200 g SiO₂) with methanol as eluant. The fractions whichaccording to GLC contained the desired product in pure form werecontinued and the solvent evaporated. The residue was dissolved in etherand treated with HCl-saturated ether giving a crystalline precipitate.Filtration and washing gave 0.18 g (20%) of the desired hydrochloride,mp. 184°-190° C.

Example E10. N-n-Propyl-3-[3-(2,6-dimethylbenzoyloxy)phenyl]piperidinehydrochloride (Method c)

A mixture of N-n-Propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (1.0g, 0.00033 mol) 2,6-dimethylbenzoyl chloride (2.15 g, 0.0127 mol) anddistilled dry pyridine (7 ml) was stirred at room temperature under N₂-atmosphere for 24 h. Aqueous NaHCO₃ was added and the mixture wasextracted with ether. The organic phase was dried and all the solventswere evaporated giving an oily residue. The residue was eluted throughan alumina column with ether and then through a silica gel column withlight petroleum-ether (1:1) as eluant. The product was then precipitatedby addition of HCl-saturated ether. Filtering and drying yielded 1.2 g(93%) of the pure desired hydrochloride, mp. 190°-191° C.

According to the methods of the Examples above the following compoundswere prepared and recrystallized as acid addition salts fromethanol/ether or isolated as the bases.

    __________________________________________________________________________     ##STR37##                                                                                             Method                                                                              Melting                                                                 (Ref. to                                                                            point (°C.)                             Example              Salt/                                                                             Example                                                                             or other                                                                              Yield.sup.(a)                          No.  n Y   R         Base                                                                              No.)  data    %                                      __________________________________________________________________________    I8   2 OCH.sub.3                                                                         H         HCl A2, h 137-138.5.sup.( *.sup.)                                                               93                                          2 OCH.sub.3                                                                         CH.sub.3  HCl A2, h 153-154.sup.( *.sup.)                                                                 68                                                              (Ex. I6)                                                  2 OCH.sub.3                                                                         C.sub.2 H.sub.5                                                                         HCl A2, h 149-150.sup.( *.sup.)                                                                 46                                                              (Ex. I6)                                             I2   1 OCH.sub.3                                                                         n-C.sub.3 H.sub.7                                                                       base                                                                              A1, e Bp 85-86/0.1.sup.( *.sup.)                                                            83                                     I6   2 OCH.sub.3                                                                         n-C.sub.3 H.sub.7                                                                       HBr A2, h 155-156.sup.( *.sup.)                                                                 70                                     I4   2 OCH.sub.3                                                                         n-C.sub.3 H.sub.7                                                                       HCl A1, d 191     72                                     I1   2 OCH.sub.3                                                                         n-C.sub.4 H.sub. 9                                                                      HCl A1, e 130-131.sup.( *.sup.)                                                                 88                                     I3   2 OCH.sub.3                                                                         n-C.sub.5 H.sub.11                                                                      base                                                                              A1, d NMR.sup.(b)                                                                           25                                          2 OCH.sub.3                                                                         CH(CH.sub.3).sub.2                                                                      base                                                                              Al, d NMR.sup.(d)                                                                           43                                                              (Ex. I3)                                                  2 OCH.sub.3                                                                         CH.sub.2 C(CH.sub.3).sub.3                                                              base                                                                              A1, e NMR.sup.(e)                                                                           81                                                              (Ex. I1)                                                  2 OCH.sub.3                                                                         CH.sub.2 CHCH.sub.2                                                                     base                                                                              A1, d NMR.sup.(f)                                                                           30                                                              (Ex. I3)                                                  2 OCH.sub.3                                                                          ##STR38##                                                                              2.HCl                                                                             A1, d (Ex. I3)                                                                      165-170 dec..sup.( *.sup.)                                                              64.sup.(o)                                1 OCH.sub.3                                                                          ##STR39##                                                                              --  A1 (Ex. I2)                                                                         IR.sup.(g)                                                                            100                                         2 OCH.sub.3                                                                          ##STR40##                                                                              --  A1 (Ex. I1)                                                                         IR.sup.(h)                                                                            --                                          2 OCH.sub.3                                                                          ##STR41##                                                                              --  A1 (Ex. I1)                                                                         IR.sup.(i)                                                                            --                                          2 OCH.sub.3                                                                          ##STR42##                                                                              --  A1 (Ex. I2)                                                                         NMR, IR.sup.(j)                                                                       91                                     I9   2 NH.sub.2                                                                          n-C.sub.3 H.sub.7                                                                       base                                                                              B2    NMR.sup.(k)                                    __________________________________________________________________________

    __________________________________________________________________________     ##STR43##                                                                                                         Method                                                                              Melting                            Compound/                            (Ref. to                                                                            point (°C.)                 Example                          Salt/                                                                             Example                                                                             or other                                                                              Yield.sup.(a)              No.    n Y            R          Base                                                                              No.)  data    %                          __________________________________________________________________________    1      2 OH           CH.sub.3   HBr a(Ex. E1)                                                                           169-170.sup.( *.sup.)                                                                 70                         2      2 OH           C.sub.2 H.sub.5                                                                          HBr a(Ex. E1)                                                                           158-159.sup.( *.sup.)                                                                 60                         3      1 OH           n-C.sub.3 H.sub.7                                                                        HBr a(Ex. E1)                                                                           128-129.sup.( *.sup.)                                                                 80                         4/E1   2 OH           n-C.sub.3 H.sub.7                                                                        HBr a     146-14 147.5.sup.( *.sup.)                                                            86                         5      2 OH           n-C.sub.4 H.sub.9                                                                        HBr a(Ex. E1)                                                                           123-124.sup.( *.sup.)                                                                 73                         6/E2   2 OH           n-C.sub.5 H.sub.11                                                                       HCl a     70-80, NMR.sup.(l)                                                                    28                         7      2 OH           CH(CH.sub.3).sub.2                                                                       HCl a(Ex. E2)                                                                           144-146 23                         8      2 OH           CH.sub.2 C(CH.sub.3).sub.3                                                               HCl a(Ex. E2)                                                                           oil, NMR.sup.                                                                         14)                        9      2 OH           CH.sub.2 CHCH.sub.2                                                                      HCl a(Ex. E2)                                                                           148-150  4                         10/E3  2                                                                                ##STR44##   n-C.sub.3 H.sub.7                                                                        HCl c     173-175 55                         11     2                                                                                ##STR45##   n-C.sub.3 H.sub.7                                                                        HCl c(Ex. E4)                                                                           155     33                         12/E4  2                                                                                ##STR46##   n-C.sub.3 H.sub.7                                                                        HCl c     170     13                         13/E5  2 OH           CH.sub.2 CH.sub.2 OH                                                                     HCl d     116.5-120                                                                             41                         14     2 OH           CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                      2.HBr                                                                             a(Ex. E1)                                                                           219-220 60                         15/E6  2 OH           n-C.sub.3 H.sub.7                                                                        HCl b     143.5-146                                                                             25                         16/E7  2 OCH.sub.2 CHCH.sub.2                                                                       n-C.sub.3 H.sub.7                                                                        HCl e     NMR.sup.(p)                                                                           49                         17/E8  2                                                                                ##STR47##   n-C.sub.3 H.sub.7                                                                        HCl c     171     52                         18/E9  2                                                                                ##STR48##   n-C.sub.3 H.sub.7                                                                        HCl c     184-190 20                         19/E10 2                                                                                ##STR49##   n-C.sub.3 H.sub.7                                                                        HCl c     190-191 93                         20     2                                                                                ##STR50##   n-C.sub.3 H.sub.7                                                                        HCl c(Ex. E10)                                                                          210-214 29                         21     2                                                                                ##STR51##   CH(CH.sub.3).sub.2                                                                       HCl c(Ex. E10)                                                                          198-200 70                         22     2                                                                                ##STR52##   n-C.sub.4 H.sub.9                                                                        HCl c(Ex. E10)                                                                          82-85   62                         23     1 OH           CH(CH.sub.3).sub.2                                                                       HBr a(Ex. E1)                                                                           146-148                            24     2 OH           CH.sub.2 CH.sub.2 CH.sub.2 OH                           25     2 OH           CH.sub.2 CH.sub.2 CH.sub.2 SCH.sub.3                    26     2 OH           CH(CH.sub.2 CH.sub.3).sub.2                             __________________________________________________________________________     Footnotes?                                                                    .sup.(*.sup.) Submitted for elemental analysis (C,H,N); All the analyses      were satisfactory.                                                            .sup.(a) Calculated on the starting phenylpiperidine or pyridinylbenzene.     .sup.(b) δ(CDCl.sub.3) 0.7-3.2 (20H,m), 3.75 (3H,s), 6.6-7.0(3H,m),     7.0-7.4 (1H,m).                                                               .sup.(c) δ(CDCl.sub.3) 0.7-3.2 (26H,m), 3.75 (3H,s), 6.6-6.95           (3H,m), 6.95-7.35 (1H,m).                                                     .sup.(d) δ(CDCl.sub.3) 1.0 (6H,d), 1.0-3.1 (10H,m), 3.7 (3H,s),         6.55-6.95 (3H,m), 6.95-7.35 (1H,m).                                           .sup.(e) δ(CDCl.sub.3) 1.2 (9H,s), 1.2-3.1 (11H,m), 3.7 (3H,s)          6.6-6.9 (3H,m), 6.9-7.35 (1H,m).                                              .sup.(f) δ(CDCl.sub.3) 1.3-3.3 (11H,m), 3.8 (3H,s), 4.9-5.4 (2H,m),     5.55-6.3 (1H,m), 6.6-7.0 (3H,m), 7.0-7.4 (1H,m).                              .sup.(g) υmax 1680 (CO), 1260 (ArOCH.sub.3)                           .sup.(h) υmax 1640 (CO), 1250 (ArOCH.sub.3)                           .sup.(i) υmax 1638 (CO), 1255 (ArOCH.sub.3)                           .sup.(j) δ(CDCl.sub.3) 1.3 (9H,s), 1,4-3.0 (9H,m), 3.8 (3H,s),          6.65-6.95 (3H,m), 7.1-7.45 (1H,m); υ max 1650 cm.sup.-1.              .sup.(k) δ(CDCl.sub.3) 0.9 (3H,t), 1,15-3.25 (13H,m), 3.5 (2H,          br.s), 6.4-6.75 (3H,m), 6.95-7.3 (1H,m).                                      .sup.(l) δ(CDCl.sub.3) 0.7-3.5 (20H,m), 6.6-6.9 (3H,m),                 6.9-7.35(1H,m), 9.8 (1H,br.s).                                                .sup.(m) δ(CDCl.sub.3) 0.7-3.4 (26H,m), 6.55-6.9 (3H,m)                 6.9-7.3(1H,m), 9.55 (1H, br.s).                                               .sup.(n) δ(CD.sub.3 OD) 1.1 (9H,s), 1.7-3.6 (11H,m), 5.1 (1H,br.s),     6.6-6.95 (3H,m), 6.95-7.35 (1H,m).                                            .sup.(o) by using dimethyl2-chloroethylamine hydrochloride as alkylating      agent.                                                                        .sup.(p) δCDCl.sub.3 0.92 (3H,t), 1.2-3.2 (16H,m), 4.45-4.65 (2H,m)     5.15-5.30 (1H,m), 5.30-5.60 (2H,m), 5.80-6.40 (1H,m), 6.55-6.90 (3H,m),       7.00-7.35 (1H,m).                                                        

The following examples illustrate how the compounds of the presentinvention may be included into pharmaceutical preparations.

Example P1. Preparation of soft gelatine capsules

500 g of active substance are mixed with 500 g of corn oil, whereuponthe mixture is filled in soft gelatine capsules, each capsule containing100 mg of the mixture (i.e. 50 mg of active substance).

Example P2. Preparation of tablets

0.5 kg of active substance are mixed with 0.2 kg of silicic acid of thetrade mark Aerosil. 0.45 kg of potato starch and 0.5 kg of lactose aremixed therewith and the mixture is moistened with a starch pasteprepared from 50 g of potato starch and distilled water, whereupon themixture is granulated through a sieve. The granulate is dried andsieved, whereupon 20 g of magnesium stearate are mixed into it. Finallythe mixture is pressed into tablets each weighing 172 mg.

Example P3. Preparation of a syrup

100 g of active substance are dissolved in 300 g of 95% ethanol,whereupon 300 g of glycerol, aroma and colouring agents (q.s.) and 1000ml of water are mixed therein. A syrup is obtained.

Example P4. Preparation of an injection solution

Active substance (hydrobromide) (1 g), sodiumchloride (0.8 g) andascorbic acid (0.1 g) are dissolved in sufficient amount of distilledwater to give 100 ml of solution. This solution, which contains 10 mg ofactive substance per ml, is used in filling ampoules, which aresterilized by heating at 120° C. for 20 minutes.

Pharmacological evaluation

Drugs acting on central dopamine (DA) transmission have for long beenknown to be clinically effective in a variety of diseases originating inthe CNS, e.g. parkinsonism and schizophrenia. In the former conditionthe nigro-neostriatal hypofunction can be restored by an increase inpostsynaptic DA-receptor stimulation, whereas the latter condition canbe normalized by achieving a decrease in postsynaptic DA-receptorstimulation. So far, this decrease has been mainly accomplished eitherby (a) direct blockade of the postsynaptic DA receptors (considered tobe the mode of action for classical antipsychotic agents like e.g.haloperidol and chlorpromazine) or (b) inhibition of intraneuronalpresynaptic events essential for the maintenance of adequateneurotransmission, e.g. granular uptake and storage (cf. the neurolepticreserpine, which is known to deplete the monoamine stores via itsactions upon granular structures), transport mechanisms and transmittersynthesis.

In recent years a large body of pharmacological, biochemical andelectrophysiological evidence has accumulated, providing considerablesupport in favour of the existence of a specific population of centralautoregulatory DA receptors, so-called autoreceptors, located on thedopaminergic neuron itself (i.e. presynaptically located). Thesereceptors are part of a homeostatic mechanism that modulates nerveimpulse flow and transmitter synthesis and thus the amount of DAreleased from the nerve endings.

The well-known direct DA-receptor against apomorphine is able toactivate the DA autoreceptors as well as the postsynaptic DA receptors.At low doses, however, the effects of autoreceptor stimulation appear topredominate, whereas at higher doses the (autoreceptor-mediated)attenuation of DA transmission is outweighed by the enhancement inpostsynaptic receptor stimulation. Thus, the "paradoxical" antipsychoticand antidyskinetic effects demonstrated in man after low doses ofapomorphine are most probably to be attributed to theautoreceptor-stimulatory properties of this DA-receptor agonist. Inaccordance with this, and in view of current knowledge of the drawbackslinked to the use of DA-receptor antagonists in the therapy ofschizophrenia and other psychotic disorders, it has been suggested thatDA-receptor stimulants with a high selectivity for CNS DA autoreceptorswould offer new therapeutic principles of great value in psychiatricmedicine. At the moment no such drug is commonly known. While searchingfor new postsynaptic DA-receptor agonists (anti-Parkinson agents) wesurprisingly discovered a group of substances possessing selectiveDA-autoreceptor agonistic properties. In order to investigate this newpharmacological profile, the following experiments were performed. Forcompound numbers see table of "End Compounds" above.

Pharmacological procedures

1. Antagonism of the reserpine-induced "neuroleptic syndrome" in therat.

Depletion of the monoamine stores with reserpine brings about a"neuroleptic syndrome" characterized by hypomotility, catalepsy, musclerigidity, hunch-backed posture as well as a number of other central andperipheral signs of monoamine depletion. This syndrome can be reversedby the administration of drugs that stimulate postsynaptic DA receptorsdirectly or indirectly, e.g. apomorphine, L-Dopa. Rats (150-300 g)pretreated with reserpine (10 mg/kg i.p., 6 h before) were givencompound 4 subcutaneously at different doses. However, no antagonism ofthe reserpine-induced syndrome was observed, not even at nearly lethaldoses. In a similar manner compound 7 was tested at 20 mg/kg s.c., i.e.a dose about 100 times the ED₅₀ in Table I. No antagonism of thereserpin-induced syndrome was seen.

2. In-vivo determination of rat brain tyrosine hydroxylation.

The compounds under evaluation were tested biochemically for centralDA-receptor (pre- and/or postsynaptic) stimulating activity. The conceptof this biochemical screening method is that a DA-receptor agonist willstimulate the receptor and through regulatory feedback systems effect adecline in tyrosine hydroxylase activity and thus a subsequent reductionin the synthesis rate for DA in the presynaptic neuron. Dopa formation,as determined after invivo inhibition of the aromatic L-amino aciddecarboxylase with NSD 1015 (3-hydroxybenzyl-hydrazine hydrochloride),is taken as an indirect measure of DA synthesis rate.

Rats (150-300 g) pretreated with reserpine were given the compoundsunder evaluation. Gross behavioural observations (changes in motility,stereotypies etc) were made in order to evaluate possible postsynapticdopamine receptor activity. Subsequent administration of NSD 1015,decapitation, brain dissection (corpora striata and the limbicfore-brain), homogenization, centrifugation, ion-exchange chromatographyand spectrofluorimetric measurements (all as described in detail byWikstrom et al., in J. Med. Chem. 21, 864-867, 1978 and references citedtherein), gave the actual Dopa levels. Several doses (n=4-6) were testedin order to obtain dose-response curves for each compound and brainarea. The dose of a compound producing a half-maximal decrease in theDopa level in the rat brain part was then estimated. These values (ED₅₀)are presented in Table I.

From studies on many other compounds having autpreceptor activity aswell as postsynaptic activity we know that at a dose representing theED₅₀ value only autoreceptor activation is likely to occur. To obtainpostsynaptic activation higher doses are necessary. (At the moment nocompound with selective postsynaptic DA-stimulating activity is known).Therefore, independently of other presented evidence (above or below)concerning receptor selectivity, the ED₅₀ values are considered torepresent doses eliciting selective autoreceptor stimulation.

All the compounds in Table I were biochemichally active except for thetwo reference compounds tested, which were completely inactive even at180 μmol/kg and 90 μmol/kg respectively. Most of the active compoundshave a potency of approximately the same order (ED₅₀ 0.6-4.4). Thesecompounds are considered to be the most suitable for medical use.Compounds with an ED₅₀ value of about 45 μmol/kg as forN-propyl-3-(3-hydroxyphenyl)pyrrolidine may be considered to be ofborderline interest.

The absence of significant postsynaptic DA-receptor activation at anydose tested indicates that all the active compounds have selectivity forthe autoreceptors (further investigated only for compound 4).

3. Antagonism of γ-butyrolactone (GBL)-induced increase in rat brain DAsynthesis rate.

The administration of GBL in anesthetic doses inhibits nerve impulseflow in central DA neurons, thus resulting in a loss of theimpulse-mediated feedback control of tyrosine hydroxylase activity andin a subsequent increase in transmitter synthesis rate (which isdetermined as described under 2 above). Since the GBL inhibitionprecludes neuronal feedback actions, antagonistic effects exerted byDA-receptor agonists upon the GBL-induced increase in synthesis are inall probability to be ascribed to their stimulating the DA autoreceptorspresent in the terminal area of the DA neurons.

Rats (150-300 g), were given compound 4 subcutaneously at several doses(n=7) followed by GBL (750 mg/kg i.p., 5 min later) and NSD 1015 (100mg/kg i.p., 10 min later). By a subsequent procedure according to 2above the Dopa levels (representing the DA-synthesis rates) weredetermined. In this model compound 4 dose-dependently antagonized theGBL-induced increase in DA synthesis rate (Loagarithmically adjusteddose-response data in Table II). The maximal reversal of the GBL-inducedincrease in DA synthesis rate was approximately 160% in the limbicsystem and 110% in corpus striatum. Furthermore, the antogonism could beblocked by haloperidol, hence confirming that the effects are due toactions on DA autoreceptors (Table III).

4. Effect on spontaneous locomotor activity in the rat.

Untreated animals exposed to a new environment display an initial highmotor activity which then gradually declines over a period of time.Administration of DA-receptor agonists (e.g. apomorphine) in doses wherepreferential autoreceptor stimulation is likely to occur, causes adepression of the spontaneous motility mentioned above, considered to bedue to the DA autoreceptor-mediated impairment of central DAtransmission. Rats (150-300 g) were injected subcutaneously with severaldoses of compounds 4 and after 5 minutes they were individually placedin motility boxes ("M/P 40 Fc Electronic Motility Meter". MotronProducts, Stockholm) and the motor activity (0-30 min) was quantified.Compound 4 exhibits a clear dose-dependent decrease of the initial highmotor activity, the maximal effect, being a 75% decrease from controlvalues, attained at about 8 mg/kg. No locomotor stimulation was everseen, regardless of the dose used. Pretreatment with a low dose ofhaloperidol (0.02 mg/kg i.p., 30 min before), in order to selectivelyblock DA-autoreceptor sites, at least partly reversed the sedativeeffect obtained with a low dose (0.5 mg/kg) of compound 4 (Table IV).Moreover, there seems to be a correlation between the decrease inspontaneous locomotion and the degree of antagonism of the GBL-inducedincrease in DA synthesis (cf. 3 above) in the limbic areas of rat brainexerted by compound 4. The percent decrease of motor activity beingroughly 0.6 times the percent reversal of GBL-induced increase inDA-synthesis rate.

5. Turning behavior in rats with acute unistriatal lesion.

In animals with an acute unilateral KCl-lesion (1 μl 25% KCl lesionedside, 1 μl 20% NaCl control side, administered through previouslyimplanted "guide cannulaes") of the striatum, compensatorycounterbalancing adjustments in the intact contralateral striatum arebrought about and therefore no appreciable asymmetry in body posture ortorsion is observed. Disturbances in the balance produces, depending onthe point of attack, ipsi- or alternatively contralateral turning. Inthis model postsynaptically active DA agonists (e.g. apomorphine, highdosage) elicit ipsilateral turning and rotatory behavior whereas DAantagonists (e.g. haloperidol) cause contralateral turning. Consequentlyit could be expected that agents acting exclusively on DA autoreceptorswould produce contralateral turning in the lesioned animals.

Rats (150-300 g) pretreated as above were given compound 4subcutaneously at several dose levels and then the animals were observedfor at least 4 h. As predicted herein, it was demonstrated that compound4, in each dose tested, made the animals turn to the side contralateralto the lesion (Table V). Moreover, their overall appearance wasindicative of a sedative action exerted by compound 4, thuscorroborating the previous findings (cf. 4 above). It was also shownthat the ipsilateral turning and rotatory response after administrationof postsynaptically effective doses of apomorphine (1.0 mg/kg s.c) wasnot affected by pretreatment with compound 4 (Table V).

6. Other observations.

Further preliminary investigations on the pharmacoligical profile ofcompound 4 have indicated that it, in contrast to agents stimulatingpostsynaptic DA receptors, is devoid of emetic activity in dogs (atleast at 1 mg/kg i.m.). As opposed to postsynaptically acting DAagonists, compound 4 (8 mg/kg s.c.) also failed to lower the rat rectaltemperature (0-30 min). It was in fact lacking any measurabletemperature effects.

7. A comparative study of compound 4 and its 3,4-dihydroxyanalogue knownfrom DE Offenlegungsschrift No. 621 536.

Rats (150-300 g) pretreated with reserpine (10 mg/kg i.p., 6 h before)were given either phys. saline, compound 4 (100 μmol/kg),N-n-propyl-3-(3,4-dihydroxyphenyl)piperidine (100 μmol/kg) orapomorphine (2 μmol/kg) subcutaneously and the locomotor activity(accumulated counts 0-60 min) was quantified by means of Motron boxes(see under 4 above). The results (Table VI) show that, apart from theirDA-autoreceptor actions (ED₅₀ :s; of, 2 above),N-n-propyl-3-(3,4-dihydroxyphenyl)piperidine as well as apomorphine,exhibit strong central postsynaptic DA-receptor stimulatory effects. Incontrast to the latter agonists, compound 4 appeared to selectively acton the DA autoreceptors and hence failed to elicit a motor response thatdiffered more than slightly from control values.

Conclusion

The pharmacological data affirm the hypothesis that the compounds underconsideration are centrally acting selective DA autoreceptor stimulatingagents, and thus of great clinical interest in the treatment ofpsychotic disorders such as schizophrenia and a number of other diseasestates such as tardive dyskinesia, Huntington's chorea,hypoprolactinemia, alcoholism and drug abuse, said psychotic disordersand other disease states possibly being associated with a pathologicalincrease in central DA transmission.

                                      TABLE I                                     __________________________________________________________________________     ##STR53##                                                                    Compound                       Salt/                                                                             ED.sub.50 *                                                                       (μmol/kg s.c.)                      No.   n Y            R         Base                                                                              Limbic                                                                            Striatum                               __________________________________________________________________________    1     2 OH           CH.sub.3  HBr 2.1 1.5                                    2     2 OH           C.sub.2 H.sub.5                                                                         HBr 4.4 4.2                                    3     1 OH           n-C.sub.3 H.sub.7                                                                       HBr ˜45                                                                         ˜45                              4.sup.(3)                                                                           2 OH           n-C.sub.3 H.sub.7                                                                       HBr 2.7 2.7                                    5     2 OH           n-C.sub.4 H.sub.9                                                                       HBr 1.7 0.7                                    6     2 OH           n-C.sub.5 H.sub.11                                                                      HCl 0.9 0.6                                    7.sup.(3)                                                                           2 OH           CH(CH.sub.3).sub.2                                                                      HCl 0.8 0.7                                    9     2 OH           CH.sub.2 CHCH.sub.2                                                                     HCl 4.2 4.0                                    10    2                                                                                ##STR54##   n-C.sub.3 H.sub.7                                                                       HCl 1.2 1.5                                    11    2                                                                                ##STR55##   n-C.sub.3 H.sub.7                                                                       HCl 2.2 1.7                                    12.sup.(3)                                                                          2                                                                                ##STR56##   n-C.sub.3 H.sub.7                                                                       HCl 1.8 2.0                                    13    2 OH           CH.sub.2 CH.sub.2 OH                                                                    HCl ˜20                                                                         ˜20                              14    2 OH           CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                     2-HBr                                                                             ˜20                                                                         ˜20                              16.sup.(3)                                                                          2 OCH.sub.2 CHCH.sub.2                                                                       n-C.sub.3 H.sub.7                                                                       HCl <45 <45                                    17.sup.(3)                                                                          2                                                                                ##STR57##   n-C.sub.3 H.sub.7                                                                       HCl <45 <45                                    18    2                                                                                ##STR58##   n-C.sub.3 H.sub.7                                                                       HCl <45 <45                                    19.sup.(3)                                                                          2                                                                                ##STR59##   n-C.sub.3 H.sub.7                                                                       HCl <45 <45                                    20.sup.(3)                                                                          2                                                                                ##STR60##   n-C.sub.3 H.sub.7                                                                       HCl <45 <45                                    21.sup.(3)                                                                          2                                                                                ##STR61##   CH(CH.sub.3).sub.2                                                                      HCl 0.5 0.5                                    22    2                                                                                ##STR62##   n-C.sub.4 H.sub.9                                                                       HCl <2.7                                                                              <2.7                                   23    1 OH           CH(CH.sub.3).sub.2                                                                      HBr                                                  2 OCH.sub.3    n-C.sub.3 H.sub.7                                                                       HBr I.sup.(1)                                                                         I.sup.(1)                                    1 OH           H         HBr I.sup.(2)                                                                         I.sup.(2)                              __________________________________________________________________________     I = inactive. .sup.(1) ED.sub.50 >180 μmol/kg. .sup.(2) ED.sub.50 >90      μmol/kg.                                                                   *Gross behavioural observations revealed no significant postsynaptic          DAreceptor activation.                                                        .sup.(3) Also tested with oral administration in the rat at 180 μmol/k     without pretreatment with reserpine. All the compounds tested were active     in reducing dopa accumulation.                                           

                  TABLE II                                                        ______________________________________                                                     % Reversal of GBL-induced                                                     increase in dopamine synthesis                                   Compound 4   rate                                                             mg/kg s.c.   Limbic system                                                                             Corpus striatum                                      ______________________________________                                        0.5          58           0                                                   1.0          75          17                                                   2.0          92          34                                                   4.0          109         51                                                   8.0          126         68                                                   16.0         142         86                                                   ______________________________________                                    

                  TABLE III.                                                      ______________________________________                                        Blockade of compound 4-induced reversal of                                    the GBL-elicited increase in DA synthesis                                     rate.                                                                                    Dopa concentration ng per                                                     g tissue        Number of                                          Treatment    Limbic system                                                                             Striatum  animals                                    ______________________________________                                        Control (NaCl)                                                                             307 ± 13.sup.                                                                          860 ± 40                                                                             18                                         Control (GBL)                                                                              506 ± 24.sup.                                                                          2366 ± 103                                                                           18                                         Compound 4 (32 mg/                                                                         191 ± 16.sup.1                                                                         1063 ± 74.sup.1                                                                      5                                          kg s.c.) + GBL                                                                Haloperidol (1 mg/                                                                         387 ± 32.sup.2                                                                         2193 ± 53.sup.2                                                                      3                                          kg i.p.) + (32 mg/kg                                                          compound 4)                                                                   ______________________________________                                         .sup.1 Siginificant, p < 0.001 versus GBLcontrol values (B).                  .sup.2 Not significant, p < 0.05 versus GBLcontrol values (B).           

                  TABLE IV                                                        ______________________________________                                        Antagonism of the compound 4-induced depression                               of locomotor activity in rats.                                                                 Motor activity                                                                (acc. counts  Number of                                      Treatment        0-15 min)     animals                                        ______________________________________                                        Glucose (i.p., 25 min                                                                          117 ± 17   6                                              before measurement) +                                                         physiological saline                                                          (s.c. 5 min before                                                            measurement)                                                                  Haloperidol (0.02 mg/kg                                                                        140 ± 22   5                                              i.p., 25 min before                                                           measurement) + physio-                                                        logical saline (s.c., 5                                                       min before measurement)                                                       Glucose (i.p., 25 min                                                                          43 ± 9     5                                              before measurement) +                                                         compound 4 (0.5 mg/kg s.c.,                                                   5 min before measurement)                                                     Haloperidol (0.02 mg/kg                                                                         80 ± 10.sup.1                                                                           7                                              i.p., 25 min before                                                           measurement) + compound 4                                                     (0.5 mg/kg s.c., 5 min                                                        before measurement)                                                           ______________________________________                                         .sup.1 Significantly different from group C, p < 0.025.                  

                  TABLE V                                                         ______________________________________                                        Turning behaviour in rats with acute unistriatal KCl lesion.                  Compound 4                                                                                                          Apomor-                                 Dose  Num-    Turning                 phine-.sup.(c)                          mg/kg ber of  Ipsi    Contra                                                                              Cata- Duration                                                                              induced                             s.c.) animals lateral lateral                                                                             lepsy.sup.(a)                                                                       of turning                                                                            turning                             ______________________________________                                        32    8       0       8     +     >4 h    Ipsi 8/8                            8     4       0       4     -     >4 h    Ipsi 4/4                            4     2       0       2     -     NT.sup.(b)                                                                            NT                                  2     4       0       4     -     >2 h    Ipsi 4/4                            1     2       0       2     -     NT      NT                                  ______________________________________                                         .sup.(a) + present, - absent                                                  .sup.(b) NT = not tested                                                      .sup.(c) apormorphine 1.0 mg/kg s.c. injected 1 h after compound 4.      

                                      TABLE VI                                    __________________________________________________________________________    Comparison of compound 4 with two known dopaminergic agonists.                                  Motor activity                                                                         Number                                                                             ED.sub.50 (μmol/kg s.c.)                                     (acc. counts                                                                           of   (cf. table 1)                                 Treatment         0-60 min postinj.)                                                                     animals                                                                            Limbic                                                                             Striatum                                 __________________________________________________________________________    Control (0.9% saline)                                                                           15 ± 5                                                                              4    --   --                                       Compound 4 (100 μmol/kg s.c.)                                                                55 ± 4                                                                              3    2.7  2.7                                      N--n-propyl-3-(3',4'-dihydroxy-                                                                 522 ± 83                                                                            3    9.4  10.0                                     phenyl)-piperidine (100 μmol/kg s.c.)                                      Apomorphine (2 μmol/kg s.c.)                                                                 624 ± 51                                                                            4     0.19                                                                              0.22                                     __________________________________________________________________________

Best mode of carrying out the invention

The compound N-n-propyl-3-(3-hydroxyphenyl)piperidine and its salts,processes for preparing said compound and methods of employing saidcompound in therapy represent the best mode of carrying out theinvention known at present. Other compounds of great value are

N-butyl-3-(3-hydroxyphenyl)piperidine,

N-pentyl-3-(3-hydroxyphenyl)piperidine, and

N-isopropyl-3-(3-hydroxyphenyl)piperidine.

We claim:
 1. A compound characterized by the formula ##STR63## wherein nis 1 or 2, Y is OH, R¹ COO--, R² R³ NCOO-- or R⁴ O whereby R¹ is analkyl group having 1-5 carbon atoms, a phenyl, 2,6-dimethylphenyl or 3-or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxyphenyl group with theformula ##STR64## wherein R⁵ is an alkyl group having 1-6 carbon atoms,R² is an alkyl group having 1-5 carbon atoms, a phenethyl, benzyl orphenyl group, R³ is an H or an alkyl group having 1-5 carbon atoms, andR⁴ is an allyl or benzyl group, and R is an alkyl group having 1-5carbon atoms, a hydroxyalkyl, dimethylaminoalkyl or methylthioalkylgroup having 2-6 carbon atoms in the alkyl part and having theheteroatom bound in a position other than the 1 position, an alkenylgroup having 3-5 carbon atoms other than a 1-alkenyl group, as the baseor a pharmaceutically acceptable acid addition salt thereof.
 2. Acompound according to claim 1, characterized in that n is 2, Y is OH, R¹COO-- or R² R³ NCOO--, whereby R¹ is an alkyl group having 1-5 carbonatoms, or a phenyl group, and R² is an alkyl group having 1-5 carbonatoms, a phenethyl, benzyl or phenyl group, and R³ is H or an alkylgroup having 1-5 carbon atoms, and R is an alkyl group having 1-5 carbonatoms, a hydroxyalkyl group having 2-6 carbon atoms in the alkyl partother than a 1-hydroxyalkyl group, an alkenyl group having 3-5 carbonatoms other than a 1-alkenyl group.
 3. A compound according to claim 1or 2 characterized in that Y is OH, R¹ COO, or R⁴ O.
 4. A compoundaccording to claims 1 or 2 characterized in that R is an alkyl grouphaving 3-5 carbon atoms.
 5. A compound according to claim 1 wherein Y isOH selected fromN-n-propyl-3-(3-hydroxyphenyl)piperidine,N-butyl-3-(3-hydroxyphenyl)piperidine,N-pentyl-3-(3-hydroxyphenyl)piperidine, orN-isopropyl-3-(3-hydroxyphenyl)piperidine,or an ester of such compoundwherein Y is R¹ COO--, as the base or a pharmaceutically acceptable acidaddition salt thereof.
 6. A process for preparation of a compound of theformula ##STR65## wherein n is 2, Y is OH, R¹ COO, R² R³ NCOO- or R⁴ Owhereby R¹ is an alkyl group having 1-5 carbon atoms or a possiblysubstituted phenyl group, R² is an alkyl group having 1-5 carbon atoms,a phenethyl, benzyl or phenyl group, R³ is H or an alkyl group having1-5 carbon atoms, and R⁴ is an allyl or benzyl group, and R is an alkylgroup having 1-5 carbon atoms, a hydroxyalkyl, dimethylaminoalkyl ormethylthioalkyl group having 2-6 carbon atoms in the alkyl part andhaving the heteroatom bound in a position other than the 1 position, analkenyl group having 3-5 carbon atoms other than a 1-alkenyl group, asthe base or pharmaceutically acceptable acid addition salt thereof,characterized in that(a) an ether or ester of the formula ##STR66##wherein R^(a) represents a hydrocarbon or acyl residue, and n and R areas defined above, is cleaved to form a compound of formula I wherein Yis a hydroxy group, or (b) in a compound of the formula ##STR67##wherein Z represents SO₃ H, Cl or NH₂, and n and R are as defined above,a hydroxy group is substituted for the group Z to the formation of acompound of formula I, wherein Y represents a hydroxy group, or (c) acompound of formula I ##STR68## wherein Y is OH and R is other thanhydroxyalkyl and as further defined above, and n is as defined above isconverted into a compound of the same formula wherein Y is R¹ COO-- orR² R³ NCOO-- or R⁴ O wherein R¹, R², R³ and R⁴ are as defined above, bytreating the firstmentioned compound with an appropriate carboxylic acidhalide R¹ COX or anhydride (R¹ CO)₂ O or with an appropriate carbamoylhalide R² R³ NCOX or isocyanate R² NCO, in the presence of a base or anacid, or with an appropriate allyl or benzyl halide R⁴ X in the presenceof a base, whereby X represents a halogen, or (d) a compound of theformula ##STR69## wherein n and Y are as defined above is converted intoa compound of formula I by alkylation of the nitrogen atom with anappropriate alkylating agent, or (e) an amide- or imide containingcompound of the formula ##STR70## wherein M¹ and M² are the same ordifferent and each represents --CH₂ -- or >C=O, and M³ is ##STR71## whenM¹ and M² are both --CH₂ --, and in other cases M³ is R, and R^(c) is H,an alkyl or alkoxy group containing 1-4 carbon atoms, a hydroxyalkyl,dimethylaminoalkyl or methylthioalkyl group containing 1-5 carbon atomsor an alkenyl group containing 2-4 carbon atoms, and R^(d) is H, R¹ CO,allyl or benzyl, and R and R¹ are as defined above, is converted into acompound of the formula I wherein Y is a hydroxy, allyl or benzyl groupby reduction of the amide or imide function, and the ester function R¹COO if present, or (f) a compound of the formula ##STR72## wherein R^(e)is H or benzyl and wherein R is an alkyl, hydroxyalkyl,dimethylaminoalkyl or methylthioalkyl group as further defined above, isconverted either by direct reduction or by first elimination of thetertiary alcohol to an intermediary 1-cycloalkenyl compound and thenreduction into a compound of formula I wherein Y is OH and R is as justdefined, or (h) a compound of the formula ##STR73## wherein Y¹ isbenzyloxy or Y, wherein Y is as defined above however other thanO-allyl, and R is an alkyl group containing 1-5 carbon atoms, or ahydroxyalkyl, dimethylaminoalkyl or methylthioalkyl group containing 2-6carbon atoms and having the heteroatom bound in a position other thanthe 1-position, is converted by reduction into the correspondingcompound of formula I wherein n is 2, whereby when Y¹ is benzyloxy acompound of formula I wherein Y is OH is obtained, or (i) a compoundaccording to the formula ##STR74## wherein one of the group Z¹ and Z² isa leaving group and the other is NHR, or Z¹ and Z² are both leavinggroups and n and R are as defined above, is converted to a compound offormula I wherein Y is OH by treating the compound of formula VIII, orwhen one of Z¹ and Z² is NHR an acid addition salt thereof, with a base,whereby the compound of formula VIII is treated together with anequivalent amount of an amine R-NH₂ or an acid addition salt thereofwhen Z¹ and Z² are both leaving groups; whereupon optionally a baseobtained is converted to a pharmaceutically acceptable acid additionsalt or a salt obtained is converted to the base or to a different,pharmaceutically acceptable acid addition salt, and optionally anisomeric mixture obtained is separated to a pure isomer.
 7. A processaccording to claim 6, characterized in that n, Y and R are as defined inany of claims 2-5.
 8. A novel compound of the formula ##STR75## whereinZ³ is R or R⁶ CO, wherein R is an alkyl group having 1-5 carbon atoms, ahydroxyalkyl, dimethylaminoalkyl or methylthioalkyl group having 2-6carbon atoms in the alkyl part and having the heteroatom bound in aposition other than the 1-position, an alkenyl group having 3-5 carbonatoms other than an 1-alkenyl group, and R⁶ is an alkyl or alkoxy groupcontaining 1-4 carbon atoms or an alkenyl group with 2-4 carbon atoms,R⁷ is an alkyl group with 1-5 carbon atoms, an allyl or benzyl group,and n is 2 provided that Z³ is other than methyl and ethyl when n is 2and R⁷ is CH₃, or an acid addition salt thereof.
 9. A pharmaceuticalpreparation comprising as an active ingredient an amount of a compoundin accordance to one of claims 1 to 5 therapeutically effective to treatdisorders in the central nervous system associated with a pathologicalincrease in the central dopamine transmission.
 10. A method of treatmentof disorders in the central nervous system associated with apathological increase in central dopamine transmission comprisingadministering to a host in need of treatment of a therapeuticallyeffective amount of a compound according to claims 1 or
 2. 11. A methodof treatment according to claim 10 wherein said central nervous systemdisorder is a psychotic disorder.
 12. A compound characterized by theformula ##STR76## wherein n is 2, Y is OH, R¹ COO, R² R³ NCOO-- or R⁴ O,wherein R¹ is an alkyl group having 1-5 carbon atoms or phenyl, 2,6dimethyl phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl or a 3- or4-alkanoyloxyphenyl group of the formula ##STR77## wherein R⁵ is analkyl group having 1-6 carbon atoms, R² is an alkyl group having 1-5carbon atoms, a phenethyl, benzyl, or phenyl group, R³ is H or an alkylgroup having 1-5 carbon atoms, and R⁴ is an alkyl or benzyl group and Ris an alkyl group having 1-5 carbon atoms, a hydroxyalkyl,dimethylaminoalkyl or methylthioalkyl group having 2-6 carbon atoms inthe alkyl part and having the heteroatom bound in a position other thanthe 1 position, an alkenyl group having 3-5 carbon atoms other than a1-alkenyl group, as the base or a pharmaceutically acceptable acidaddition salt thereof.
 13. A compound according to claim 12,characterized in that Y is OH, R¹ COO-- or R² R³ NCOO-- whereby R¹ is analkyl group having 1-5 carbon atoms, or a phenyl group, and R² is analkyl group having 1-5 carbon atoms, a phenethyl, benzyl or phenylgroup, and R³ is H or an alkyl group having 1-5 carbon atoms, and R isan alkyl group having 1-5 carbon atoms, a hydroxyalkyl group having 2-6carbon atoms in the alkyl part other than a 1-hydroxyalkyl group, analkenyl group having 3-5 carbon atoms other than a 1-alkenyl group. 14.A compound according to claims 12 or 13 characterized in that Y is OH,R¹ COO, or R⁴ O.
 15. A compound according to claims 12 or 13characterized in that R is an alkyl group having 3-5 carbon atoms.
 16. Anovel compound of the formula ##STR78## wherein Z³ is R or R⁶ CO,wherein R is an alkyl group having 1-5 carbon atoms, a hydroxyalkyl,dimethylaminoalkyl or methylthioalkyl group having 2-6 carbon atoms inthe alkyl part and having the heteroatom bound in a position other thanthe 1-position, an alkenyl group having 3-5 carbon atoms other than an1-alkenyl group, and R⁶ is an alkyl or alkoxy group containing 1-4carbon atoms or an alkenyl group with 2-4 carbon atoms, R⁷ is an alkylgroup with 1-5 carbon atoms, an allyl or benzyl group, and n is 2,provided that Z³ is other than methyl and ethyl when R⁷ is CH₃, or anacid addition salt thereof.
 17. A pharmaceutical preparation containinga therapeutically effective amount of the compound in accordance withclaims 12 or 13 in conjunction with the pharmaceutically acceptablecarrier.
 18. The method for the treatment of disorders in the centralnervous system associated with a pathological increase in centraldopamine transmission comprising administering to a host in need of suchtreatment of a therapeutically effective amount of a compound inaccordance with claims 12 or
 13. 19. A method of treatment according toclaim 18 wherein said central nervous system disorder is a psychoticdisorder.